1. Technical Field
The present invention generally relates to a system and a method for delaying the dissolution of blood clots, and more particularly, the present invention provides a method and a delivery system for a material which delays the degradation of fibrin based blood clots.
2. Background of the Invention
Fibrin is insoluble protein produced by the body in response to bleeding, and is a major component in blood clots. Fibrin based clots form naturally during hemostasis, which is a process that stops bleeding by converting blood from a liquid to a solid. Fibrin is formed from fibrinogen, a soluble protein produced by the liver. Fibrinogen is converted at a wound site into fibrin by the action of thrombin, a clotting enzyme, in instances of tissue damage. Fibrin molecules may combine to form fibrin threads that mesh with platelets to form an initially soft mass. The soft mass may later harden and contract to form a rigid blood clot.
A fibrin gel may be used as a natural scaffold in tissue engineering. In one instance, a cross-linked fibrin sealant may be synthesized in vitro by combining aqueous solutions of fibrinogen and thrombin in the presence of a calcium ion (e.g., calcium chloride). This produces a fibrin sealant that resembles a physiological clot. Such fibrin sealants may be useful in surgery as an adjunct to sutures and staples. For example, severe, deep and/or artificial (i.e. as caused by a surgical incision) wounds may require that sealant mechanical strength and tissue bonding be retained until the wound fully heals. This process may take as long as fourteen days. Therapeutics is another area of use for fibrin sealants, for example in the treatment of Menorrhagia (heavy menstrual bleeding, “HMB”, whereby such sealants may be administered orally or intravenously).
Fibrin sealants degrade in the presence of proteases and other enzymes in the body. For example, fibrin sealants degrade in two to three days in vivo from proteases, such as plasmin, in a wet environment. Plasmin is a serine protease. The body then absorbs the remnants of the fibrin sealant.
Rapid degradation of clots is not always welcome, particularly when deep wounds take longer to heal. Degradation of tissue engineered fibrin constructs may be delayed in vitro by fibrinolytic inhibitors, such as, aprotinin. Aprotinin, a protease inhibitor, slows or stops fibrinolysis by inhibiting plasmin. However, currently available treatments using Aprotinin often struggle to provide a safe and reliable therapeutic method to delay the degradation of fibrin clots, or fibrinolysis.
An alternative fibrinolysis inhibitor is trans-4-aminomethyl-cyclohexane-1-carboxylic acid, commonly referred to as tranexamic acid (TA). TA, often recommended for cardiac surgery, reversibly blocks lysine-binding sites on plasminogen, a plasmin proenzyme present in blood. By blocking lysine-binding sites on plasminogen, TA delays the conversion of plasminogen to plasmin, effectively slowly fibrinolysis. Thus less plasmin is available to dissolve and/or degrade fibrin-based blood clots.
As stated above, lower plasmin levels result in a longer fibrinolysis and degradation profile for a given fibrin-based blood clot. Applications of TA as an alternative to Aprotinin in fibrin-based cardiovascular tissue engineering is further discussed in a paper by E. Cholewinski et al., Tissue Engineering: Part A, Vol. 15, No. 11, pp 3645-3646, 3650-3652, 2009.
Research demonstrates that a TA derivative bio-adhesive swelling matrix may prevent bleeding in oral and maxillofacial surgery. The TA swelling matrix demonstrates appropriate mechanical resistance. Also, the TA swelling matrix rapidly swells to form a mico-adhesive plug upon contact with blood. The plug then may then disintegrate upon TA delivery. Localized delivery of a hemostatic agent, namely TA, in chronically anti-coagulated patients is further discussed by G. Sammartino et al., J. Carniofacial Surgery, Vol. 23, No. 6, pp 648-652, November 2012.
The protease inhibitors Aprotinin and TA, are highly water soluble and, therefore, may diffuse from a sealant, such as a fibrin sealant, under in vivo conditions. The diffusion properties and behavior of protease inhibitors from a fibrin sealant is further discussed in a paper by C. Buchta et al., Biomaterials, Vol. 26, Iss. 31, pp 6233-6241, November 2005.
Currently available technology may not adequately meet the challenges presented by the undesirable diffusion of a protease inhibitor, such as TA, from a sealant. In example, various drug delivery methodologies directed toward the controlled diffusion of embedded anti-fibronolytic agent largely disclose an initial burst of the agent followed by a slow release, rather than a prolonged and uniform delivery mechanism as often necessary for lengthy wound treatment therapies.